Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex.
Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex.
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DOI：
10.1186/s13229-015-0049-5
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发表时间：
2015
期刊：
影响因子：
6.2
通讯作者：
Nagata K
中科院分区：
文献类型：
--
作者：
Hamada N;Ito H;Iwamoto I;Morishita R;Tabata H;Nagata K
RBFOX1(也称为FOX1或A2BP1)调节对神经元功能至关重要的各种转录本的选择性剪接。RBFOX1在大脑发育过程中的生理意义似乎是必不可少的，因为该基因的异常会导致自闭症谱系障碍(ASD)和其他神经发育和神经精神障碍，如智力残疾、癫痫、注意缺陷多动障碍和精神分裂症。在ASD基因转录组网络中，RBFOX1也是一个“中枢”。然而，RBFOX1基因异常的病理生理学意义仍有待阐明。为了阐明RBFOX1的病理生理学相关性，我们对小鼠皮质化过程中脑特异性胞浆异构体RBFOX1-ISO2进行了一系列体内和体外分析。体内分析基于宫内电穿孔，并通过包括激光共聚焦显微镜辅助时间推移成像在内的形态学方法研究RBFOX1-ISO2在皮质神经元迁移、神经发生和形态中的作用。对原代培养的小鼠海马神经元进行了体外分析。在子宫中沉默RBFOX1-ISO2导致皮质神经元在皮质发生过程中径向迁移和末端移位的缺陷。时间推移成像显示，径向迁移明显受到核动学失调的影响。RBFOX1-ISO2还调节体内神经元网络的形成，因为轴突延伸到对侧大脑半球和树突分枝受到基因敲除的阻碍。在体外分析中，RBFOX1-ISO2缺陷的海马神经元的脊椎密度和成熟脊椎数量减少。在脑发育过程中，RBFOX1-ISO2功能受损会导致皮质生成异常。这一异常过程可能是ASD和其他神经发育障碍的基本病理生理基础，也可能是RBFOX1基因异常患者出现临床症状的原因之一。本文的在线版本(doi：10.1186/s13229-0150049-5)包含补充材料，授权用户可以使用。
RBFOX1 (also known as FOX1 or A2BP1) regulates alternative splicing of a variety of transcripts crucial for neuronal functions. Physiological significance of RBFOX1 during brain development is seemingly essential since abnormalities in the gene cause autism spectrum disorder (ASD) and other neurodevelopmental and neuropsychiatric disorders such as intellectual disability, epilepsy, attention deficit hyperactivity disorder, and schizophrenia. RBFOX1 was also shown to serve as a “hub” in ASD gene transcriptome network. However, the pathophysiological significance of RBFOX1 gene abnormalities remains to be clarified. To elucidate the pathophysiological relevance of Rbfox1, we performed a battery of in vivo and in vitro analyses of the brain-specific cytoplasmic isoform, Rbfox1-iso2, during mouse corticogenesis. In vivo analyses were based on in utero electroporation, and the role of Rbfox1-iso2 in cortical neuron migration, neurogenesis, and morphology was investigated by morphological methods including confocal laser microscope-assisted time-lapse imaging. In vitro analyses were carried out to examine the morphology of primary cultured mouse hippocampal neurons. Silencing of Rbfox1-iso2 in utero caused defects in the radial migration and terminal translocation of cortical neurons during corticogenesis. Time-lapse imaging revealed that radial migration was apparently impaired by dysregulated nucleokinesis. Rbfox1-iso2 also regulated neuronal network formation in vivo since axon extension to the opposite hemisphere and dendritic arborization were hampered by the knockdown. In in vitro analyses, spine density and mature spine number were reduced in Rbfox1-iso2-deficient hippocampal neurons. Impaired Rbfox1-iso2 function was found to cause abnormal corticogenesis during brain development. The abnormal process may underlie the basic pathophysiology of ASD and other neurodevelopmental disorders and may contribute to the emergence of the clinical symptoms of the patients with RBFOX1 gene abnormalities. The online version of this article (doi:10.1186/s13229-015-0049-5) contains supplementary material, which is available to authorized users.